Fluid delivery apparatus

ABSTRACT

An apparatus for accurately infusing medicinal agents into an ambulatory patient at specific rates over extended periods of time. The apparatus is of a compact, low profile, laminate construction and includes an elastic distendable membrane, which, in cooperation with a thin planar base, defines a fluid chamber having a fluid outlet. Disposed within the fluid chamber is a thin fluid permeable member which precisely controls the rate of fluid flow through the fluid outlet.

This is a continuation application of Ser. No. 07/642,208. filed Jan.16, 1991, now U.S. Pat. No. 5,169,389, which is a continuation in partof Ser. No. 07/367,304 Filed Jun. 16, 1989 which has now issued to U.S.Pat. No. 5,019,047

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

The present invention relates generally to fluid delivery devices. Moreparticularly, the invention concerns an improved apparatus for infusingmedicinal agents into an ambulatory patient at specific rates overextended periods of time.

DISCUSSION OF THE INVENTION

Many medicinal agents require an intravenous route for administrationthus bypassing the digestive system and precluding degradation by thecatalytic enzyme in the digestive tract and the liver. The use of morepotent medications at elevated concentrations has also increased theneed for accuracy in controlling the delivery of such drugs. Thedelivery device, while not an active pharmacologic agent, may enhancethe activity of the drug by mediating its therapeutic effectiveness.Certain classes of new pharmacologic agents possess a very narrow rangeof therapeutic effectiveness, for instance, too small a dose results inno effect, while too great a dose results in toxic reaction.

In the past, prolonged infusion of fluids has generally beenaccomplished using gravity flow methods, which typically involve the useof intravenous administration sets and the familiar bottle suspendedabove the patient. Such methods are cumbersome, imprecise and requirebed confinement of the patient. Periodic monitoring of the apparatus bythe nurse or doctor is required to detect malfunctions of the infusionapparatus.

Devices from which liquid is expelled from a relatively thick-walledbladder by internal stresses within the distended bladder are well-knownin the prior art. Such bladder, or "balloon" type, devices are describedin U.S. Pat. No. 3,469,578, issued to Bierman and in U.S. Pat. No.4,318,400, issued to Perry. The devices of the aforementioned patentsalso disclose the use of fluid flow restrictors external of the bladderfor regulating the rate of fluid flow from the bladder.

The prior art bladder type infusion devices are not without drawbacks.Generally, because of the very nature of bladder or "balloon"configuration, the devices are unwieldly and are difficult and expensiveto manufacture and use. Further, the devices are somewhat unreliable andtheir fluid discharge rates are frequently imprecise.

The apparatus of the present invention overcomes many of the drawbacksof the prior art by eliminating the bladder and making use of recentlydeveloped elastomeric films and similar materials, which, in cooperationwith a, plate-like base defines a fluid chamber that contains the fluidwhich is to be dispensed. The elastomeric film membrane controllablyforces fluid within the chamber into fluid flow channels provided in thebase. In one form of the apparatus of the invention, a thin, planarshaped flow rate control member is strategically located within thechamber to precisely control the rate of flow of the liquid toward thefluid flow channels. The flow rate control member can be very thin andcan be selected to have a very precise degree of permeability so thatthe rate of flow of fluid into the fluid flow channels can be controlledwith great accuracy.

The use of state of the art thin membranes and films permits theconstruction of compact, low profile, laminated structures which areeasy to use and inexpensive to manufacture. When the devices of theinvention are to be used with ambulatory patients they are constructedof flexible materials and are provided with a thin adhesive backingwhich permits the device to be conveniently self-affixed to thepatient's arm or other parts of the body.

The apparatus of the invention can be used with minimal professionalassistance in an alternate health care environment, such as the home. Byway of example, devices of the invention can be used for the continuousinfusion of antibiotics, hormones, steroids, blood clotting agents,analgesics, and like medicinal agents. Similarly, the devices can beused for I-V chemotherapy and can accurately deliver fluids to thepatient in precisely the correct quantities and at extended microfusionrates over time.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an apparatus forexpelling fluids at a precisely controlled rate which is of a compact,low profile, laminate construction. More particularly, it is an objectof the invention to provide such an apparatus which can be used for theprecise infusion of pharmaceutical fluids to an ambulatory patient atcontrolled rates over extended periods of time.

It is another object of the invention to provide an apparatus of theaforementioned character which is highly reliable and easy-to-use by laypersons in a non-hospital environment.

Another object of the invention is to provide an apparatus which can befactory prefilled with a wide variety of medicinal fluids or one whichcan readily be filled in the field shortly prior to use.

Another object of the invention is to provide an infusion device inwhich fluids can be delivered either at a fixed rate or at variablerates and one which is operational in all altitudes and attitudes.

Still another object of the invention is to provide an apparatus of theclass described which is soft, conformable and compliant so as toreadily conform to the patient's anatomy proximate the point ofinfusion.

Yet another object of the invention is to provide an apparatus asdescribed in the preceding paragraph which is provided with a thin,flexible foam backing with adhesive for self-attachment. The apparatuscan be unobtrusively worn under clothing.

A further object of the invention is to provide a low profile, fluiddelivery device of laminate construction which can be manufacturedinexpensively in large volume by automated machinery.

Another object of the invention is to provide a device of the characterdescribed in which fluid is dispelled from the apparatus through eitheran integral infusion needle, or through a luer type connector, by athin, distendable membrane cooperatively associated with a thin,plate-like base.

Another object of the invention is to provide an apparatus of theaforementioned character in which the distendable member is permeable togases at least in one direction, whereby gases within the medicinalagent can be released from the fluid chamber and not injected into thepatient.

Still another object of the invention is to provide an apparatus asdescribed in the preceding paragraphs in which the rate of fluid flowfrom the apparatus is precisely controlled by a thin planar shaped,fluid permeable member which forms a part of the low profile, laminateconstruction of the apparatus.

Another object of the invention is to provide a fluid delivery deviceembodying an iostropic distendable membrane with a uniform modulus ofelasticity which cooperates with a base to define a fluid chamber havinga fluid outlet in communication with dispensing port for dispensingfluid from the device and including a flow control element disposedintermediate the fluid outlet and the dispensing port.

Still another object of the invention is to provide a device asdescribed in the preceding paragraph in which the flow control elementcomprises a restriction which controllably restricts the flow of fluidbetween the fluid outlet and the dispensing port.

A further object: of the invention is to provide a fluid delivery deviceembodying a distendable membrane assembly which cooperates with a baseto define a fluid chamber having a fluid outlet in which the distendablemembrane assembly is of multilaminate construction being made up of aplurality of individual members or layers which cooperate tocontrollably urge fluid within the fluid chamber outwardly of the fluidoutlet of the device.

Another object of the invention is to provide a fluid delivery device ofthe chamber described in the preceding paragraph which includes a ratecontrol membrane and in which the base is provided with a multiplicityof micro-channels for conducting fluid to the rate control membrane atprecise rate over a predetermined active area.

A principal object of one form of the invention is to provide a novelagent formulation dispenser adopted for use with a slightly modifiedversion of the basic fluid delivery device of the present invention foradministering an aqueous solution containing selected drugs or otherchemical compounds at a controlled rate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a generally perspective view of one form of the fluiddispensing apparatus of the invention.

FIG. 2 is an exploded, generally perspective view of the apparatus ofFIG. 1.

FIG. 3 is a top view of the apparatus partly broken away to showinternal construction.

FIG. 4 is an enlarged cross sectional view taken along lines 4--4 ofFIG. 3.

FIG. 5 is a cross sectional view taken along lines 5--5 of FIG. 4.

FIG. 6 is a fragmentary view taken along lines 6--6 of FIG. 4.

FIG. 7 is a cross sectional view taken along lines 7--7 of FIG. 4.

FIG. 8 is a view similar to FIG. 4, but illustrating the separation ofthe molded needle cover from the device.

FIG. 9 is a cross sectional view taken along lines 9--9 of FIG. 8.

FIG. 10 is a generally perspective exploded view of another embodimentof the fluid dispensing apparatus of the present invention.

FIG. 11 is a top view of the apparatus shown in FIG. 10.

FIG. 12 is a cross sectional view taken along lines 12--12 of FIG. 11.

FIG. 13 is a cross sectional view taken along lines 13--13 of FIG. 12.

FIG. 14 is a cross sectional view taken along lines 14--14 of FIG. 12.

FIG. 15 is a fragmentary view taken along lines 15--15 of FIG. 12.

FIG. 16 is a view similar to FIG. 12, but showing the molded needlecover separated from the device.

FIG. 17 is a greatly enlarged fragmentary view illustrating the methodof fluid fill of the apparatus of this form of the invention.

FIG. 18 is a generally perspective exploded view of another embodimentof the apparatus of the present invention.

FIG. 19 is a fragmentary top view of the apparatus of this form of theinvention.

FIG. 20 is a cross sectional view taken along lines 20--20 of FIG. 19

FIG. 21 is a cross sectional view taken along lines 20--20 of FIG. 19.

FIG. 22 is a generally perspective exploded view of still another formof the apparatus of the present invention.

FIG. 23 is a plan view of the apparatus of FIG. 22 partly broken away toshow internal construction.

FIG. 24 is a greatly enlarged fragmentary perspective view of a portionof the apparatus illustrating the arrangement of the rate controlmembranes of the device.

FIG. 25 is a cross sectional view taken along lines 25--25 of FIG. 23.

FIG. 26 is a fragmentary view taken along lines 26--26 of FIG. 25.

FIG. 27 is a cross sectional view taken along lines 27--27 of FIG. 25.

FIG. 28 is a cross sectional view taken along lines 28--28 of FIG. 25.

FIG. 29 is a fragmentary, cross sectional view similar to FIG. 25, butshowing the needle cover separated from the apparatus of the invention.

FIG. 30 is a generally prospective, exploded view of still anotherembodiment of the present invention.

FIG. 30A is a fragmentary plan view taken along lines 30A--30A of FIG.32 showing the internal construction of the apparatus of FIG. 30.

FIG. 30B is an enlarged cross-sectional view of the circled area shownin FIG. 32.

FIG. 31 is a fragmentary, generally perspective view of the circledportion of the flow rate control membrane as shown in FIG. 30.

FIG. 32 is a cross-sectional view of the apparatus shown in FIG. 30.

FIG. 33 is an exploded, generally perspective view of still another formthe apparatus of the invention.

FIG. 34 is a fragmentary plan view of the fluid outlet portion of theapparatus of FIG. 33, partly broken away to show internal construction.

FIG. 35 is a cross-sectional view taken along lines 35--35 of FIG. 34.

FIG. 36 is a cross-sectional view taken along lines 36--36 of FIG. 34.

FIG. 37 is a cross-sectional view taken along lines 37--37 of FIG. 36.

FIG. 38 is a fragmentary, generally perspective view of a portion of theflow control means of this form of the apparatus of the invention.

FIG. 39 is a fragmentary, generally perspective view of the distendablemembrane of the latest form of the invention illustrating the laminateconstruction thereof.

FIG. 40 is a plan view of yet another form of the invention, partlybroken away to show internal construction.

FIG. 41 is an exploded, generally perspective view of the form of theapparatus of the invention shown in FIG. 40.

FIG. 42 is a cross-sectional view taken along lines 42--42 of FIG. 40.

FIG. 43 is a cross-sectional view taken along lines 43--43 of FIG. 42.

FIG. 44 is a cross-sectional view taken along lines 44--44 of FIG. 42.

FIG. 45 is a generally perspective view of various forms of activatingmembers for activating the parenteral fluid with a medicament which areusable with this embodiment of the apparatus of the invention.

FIG. 46 is a fragmentary, cross-sectional view similar to FIG. 44illustrating the use of flow distribution materials within the liquidflow manifolds of the device.

FIG. 47 is an exploded, generally perspective view of yet anotherembodiment of the invention.

FIG. 48 is an exploded, generally perspective view of still another formof the fluid delivery apparatus of the invention.

FIG. 49 is a plan view of the apparatus partially broken away to showinternal construction.

FIG. 50 is a cross-sectional view taken along lines 50--50 of FIG. 49.

FIG. 51 is a cross-sectional view taken along lines 51--51 of FIG. 50.

FIG. 52 is an enlarged side elevational view partly in cross-section toshow internal construction of a additive carrying subassembly of theinvention.

FIG. 53 is an enlarged end view of one end cap of the additivesubassembly shown in FIG. 52.

FIG. 54 is a side elevational view partly broken away of the end capshown in FIG. 53.

FIG. 55 is an exploded view of the additive subassembly shown in FIG. 52partly in cross-section to better illustrate the construction of thesubassembly.

FIG. 56 is a fragmentary, generally perspective view of one of the endcaps of the additive subassembly of the apparatus.

FIG. 57 is an enlarged, cross-sectional view taken along lines 57--57 ofFIG. 50.

FIG. 58 is a side elevational view of the apparatus of this form of theinvention being filled by a hypodermic syringe of standard construction.

FIG. 59 is a fragmentary, side elevational view similar to FIG. 57showing the fluid flow path of the fluid flowing through the apparatusand outwardly toward the dispensing means.

FIG. 60 is a cross-sectional view taken along lines 60--60 of FIG. 57.

DESCRIPTION OF THE INVENTION

Referring to the drawings and particularly to FIGS. 1 through 9, oneembodiment of the apparatus for use in infusing medicinal fluids into apatient is there illustrated and generally designated by the numeral 12.As indicated in FIG. 1, the apparatus of this form of the inventioncomprises a laminate, or layered, structure made up of a plurality ofthin plate-like components. As best seen by referring to FIG. 2, theapparatus comprises a thin, generally planar plate-like base 14, havinga pair of flow rate control channels provided here as longitudinallyextending fluid conduits 16 and 18. Conduits 16 and 18 areinterconnected by a fluid transfer manifold, or transverse conduit 20,which, in turn, is interconnected with a fluid outlet passageway 22. Athin, generally planar distendable elastomeric membrane, or member, 24cooperates with base 14 to form a chamber 25 (FIG. 4). Member 24 isdistendable out of plane in the manner shown in FIG. 4 by theintroduction of fluid into the chamber under pressure. As thedistendable member 24 is distended by the fluid pressure, internalstresses are formed in the member which continuously urge it to returnto its original planar configuration. The method of introduction offluids into chamber 25 will presently be described. As shown in FIG. 5,to maintain the low profile character of the device, the height of thefluid chamber is substantially less than the width of base 14.

Forming an important aspect of the apparatus of the invention is theprovision of flow control means which is disposed internally of chamber25 for controlling the rate of fluid flow through the outlet 22 formedin base member 14. In the embodiment of the invention hereshown, theflow control means is provided in the form of a thin, permeable member26 which is superimposed over base 14 in the manner shown in FIG. 4. Aswill presently be described, member 26 precisely controls the rate offluid flow from chamber 25 into fluid conduits 16, 18 and 20 formed inbase 14. It is this precise control of the rate of fluid flow whichenables infusion into the patient of medicinal fluids at an extremelyprecise rate over extended periods of time ranging from several hours toin excess of 24 hours depending on sized reservoir volume.

Superimposed over flow control member 26 is a distendable membraneengagement means. This means is here provided in the form of a generallyplanar member 28 having a peripheral portion 28a to which the margins ofdistendable member 24 are bonded, as by adhesive or thermo-bonding.Member 28 also has a pair of longitudinally extending, spaced apartupstanding protruberances 30. Each of the protruberances 30 is providedwith a longitudinally extending first fluid passageway or conduit 32.When the apparatus is assembled in the manner shown in FIG. 9,passageways 32 are superimposed over fluid conduits 16 and 18 andprotruberances 30 extend upwardly into fluid chamber 26 so as to defineullage "U" within chamber 25. In operation of the device, as distendablemembrane 24 attempts to return to its original planar configuration(FIG. 9), it will move toward engagement with the upper surfaces ofprotruberances 30 and in so doing will efficiently force the fluidcontained within chamber 25 uniformly through the flow control member 26and into passageways 16 and 18. The configuration of protuberances 30ensure that all of the fluid within chamber 25 will be dispelledtherefrom as the membrane returns toward its starting configuration.Passageways 16, 18, and 32 can be alternately configured to providevarious degrees of fluid exposure to rate control membrane 26 wherebythe active surface area of membrane 26 is increased or decreased.

Superimposed over the assembly comprising base 14, distendable membrane24, flow control member 26, and distendable membrane engaging member 28is a porous plastic cover 34 which functions to provide a superstructureand a venting means for venting gases, if any, contained within themedicinal agent. Affixed to the top of cover 34 is a medicant and useinstruction label 36 which can be used to identify the medicinal fluidcontained within chamber 25 of the device.

Affixed to the bottom of base 14 is a cushioning means shown here as athin, planar shaped foam pad 38. Foam pad 38 is provided with adhesiveon both its upper and lower surfaces. The adhesive on the upper surfaceof pad 38 enables the pad to be affixed to the lower surface of base 14.As indicated in FIGS. 2 and 4, a peel strip 40 is connected to thebottom surface of foam pad 38 by the adhesive provided thereon. When thedevice is to be used, peel strip 40 can be stripped away from pad 38 sothat the adhesive on the lower surface of the foam pad 38 can be used toreleasably affix the apparatus of the invention to the anatomy of thepatient.

Turning now to FIGS. 4 and 8, a needle assembly 42 is integrally formedwith base 14. Needle assembly 42 which includes a distal portion 42a anda proximal portion 42b, is provided with a longitudinally extending bore44. As best seen in FIG. 4, bore 44 is in communication with outletpassageway 22 formed in base 14. Fixedly received within that portion ofpassageway 44, which extends through distal portion 42a, is a hollowinfusion needle 46 of the character typically used for injecting fluidsinto a patient. The fluid outlet end of needle 46 is received withinthat portion of passageway 44 which extends through proximal portion42b. Intermediate portions 42a and 42b is a reduced diameter frangibleportion 42c which can be broken so as to separate portions 42a and 42bto expose the outlet end of needle 46 in the manner shown in FIG. 8.Also forming a part of proximal portion 42b is a protective sheath 48for encapsulating and protecting needle 46. Needle assembly 42 alsoincludes web means for further assisting in securing and maintaining theneedle in an appropriate invasive position to preclude inter-vasculartrauma. The web means are here provided as a soft, flexible butterflyassemblage 49, which, as shown in FIGS. 1 and 7, is integrally formedwith base 14 and joined therewith by webbing 49a. Butterfly assembly 49also provides appropriate surface area for tape adhesion covering theinjection site.

Turning now to FIGS. 2, 3, 4 and 6, the distendable membrane engagementelement 28 which comprises the means for creating an ullage withinchamber 25, also includes an upstanding transversely extending portion50 having a fluid passageway 52 extending therethrough. In the presentembodiment of the invention, the open end 52a of passageway 52 is closedby a closure member 54 which is adapted to sealably close passageway 52after chamber 25 has been filled with the selected medicinal agent.Passageway 52 can also be closed by any suitable means such as thermalor mechanical sealing. As best seen by referring to FIG. 4, passageway52 is in communication with a pair of longitudinally extendingpassageways 56 formed in element 28. Passageways 56 are, in turn, incommunication with chamber 25 via passageways 58. As illustrated in FIG.2, passageways 58 extend through protuberances 30 and are disposed inthe ends of protuberances 30 located proximate transversely extendingpassageway 52.

The apparatus of this first embodiment of the invention is adapted to befilled with the selected medicinal fluid at time of manufacture. This isaccomplished by removal of plug 54 so that fluid under pressure can beforced into passageway 52 and thence into chamber 25 via passageways 56and 58. As the fluid under pressure flows through passageways 58, itwill cause the membrane 24 to distend upwardly into initial engagementwith cover 34 in the manner shown in FIG. 4. After chamber 25 has beenfilled with the medicinal fluid, closure plug 54 is bonded or otherwiseaffixed in place within the open end 52a of conduit 52 so as to sealchamber 25 with respect to atmosphere.

So long as needle assembly 42 remains intact in the manner shown in FIG.4, the fluid will be retained within chamber 25. However, upon twistingand breaking the frangible section 42c so that portion 42b of the needleassembly can be removed as shown in FIG. 8, distendable membrane 24 willbegin to expel fluid through the needle 46. The rate of expulsion offluid is, of course, controlled by the permeable membrane 26 which isdisposed intermediate the fluid flow passageways 32 of member 28 andfluid flow passageways 16 and 18 formed in base 14.

As previously mentioned, the state of the art materials used in theconstruction of the apparatus of the invention markedly contribute tothe reliability, accuracy and manufacturability of the apparatus. Beforediscussing the alternate forms of the invention shown in the drawings, abrief review of the materials used in constructing the apparatus is inorder.

With respect to the base 14, a wide variety of materials can be used,including; metals, rubber or plastics that are compatible with theliquids they contact and are preferably not non-allergenic. Examples ofsuch materials are stainless steel, aluminum, latex rubber, butylrubber, nitrile rubber, polyisiprene, styrene-butadiene copolymer,silicones, polyolefins such as polypropylene and polyethylene,polyesters, polyurethane, polyamides and polycarbonates. Manufacturersof suitable materials include; Dow Corning of Midland, Mich., GeneralElectric of Schenectady, N.Y. and Shell Chemical Company of Houston,Tex., DuPont Chemical of Wilmington, Del., and Eastman Chemical ofKingsport, Tenn.

Considering next the important flow control means, or member 26,precision microflow through this important component is a pressuredriven flow delivery process with controllable delivery rates between0.1 to 4.5 milliliters per hour. Depending on the medicinal agent to bedelivered and the required flow rate regime, several microporousmembranes can be employed, including asymmetric substrate based filmssuch as cellulose acetate, cellulose acetate buterate, and ethylcellulose. These membrane films may vary from 20 microns to 100 micronsthick and can be made of a porous substrate with a controlled skin wherethe active porosity can vary from angstroms to 50 microns in diameter.Additionally, other acrylic resins can also be used for thin film,delivery membranes such as poly-methyl-methacrylate (PMM) andpolysulfone on PVC also with approximately 2 microns thickness of skinof active membrane surface on up to 100 microns of substrate backing.Other matrix polymer systems are also candidates for microfilm membranesand include PCCE copolyesters and nylon PEBAX-polyethersteramide (PEEA),as well as PTFE, PVDF, P-P mixed ester cellulose and certain otherpolycarbonates. Manufacturers of these materials include; Bend Research(Cellulose Acetates, polysulfones), Eastman Chemical (PCCE Copolyester#9966), Atochem (PEBAX Nylon), Dupont (Hytrel), Rohm Pharmaceuticals(Acrylic Resins) and Millipore (PTFE), PVDF and mixed ester cellulose).

Considering next the elastic distendable membrane 24, this importantcomponent can be manufactured from several alternate materials includingrubbers, plastics and other thermoplastic elastomers. These includelatex rubber, polyisoprene (natural rubber), butyl rubber, nitrilerubber, other homopolymer, copolymers (random, alternating, block,graft, crosslink and starblock), mechanical poly-blends andinterpenetrating polymer networks.

Examples of materials found particularly well suited for thisapplication include; silicone polymers (polysiloxanes) (high performancesilicone elastomers made from high molecular weight polymers withappropriate fillers added). These materials are castable into thin filmmembrances and have high permeability (which allows maximum transport ofvapor and gas), high bond and tear strength and excellent lowtemperature flexibility and radiation resistance. Additionally, siliconeelastomers retain their properties over a wide range of temperature(-80° to 200° C.) are stable at high temperatures, and exhibit tensilestrengths up to 2,000 lb./in² elongation up to 600%.

Further, silicone (polyorganosiloxanes) are thermally stable,hydrophobic organometallic polymers with the lowest P-P interaction (ofall commercially available polymers. This fact coupled with theflexibility of the backbone results in a low Tg (-80° C.) and anamorphous rubbery structure for the high MW (polydimethylsiloxanes).Silicone rubber membranes are considerably more permeable to gases thanmembranes of any other polymer. Depending on the medicinal fluid usedand the filling of the storage mode, which will determine the desiredmass transport characteristics of the membrane (permeability andselectivity), other materials of choice includepolyurethane-polysiloxane copolymers, blends and IPN's. By example,polydimethylsiloxane (PDMS) and polyurethane (PU) multicomponent IPNcontaining 10%-20% weight of PU shows enhanced initial modulus relativeto that of PDMS itself.

Interpenetrating polymer networks (IPNS) are unique blends ofcross-linked polymers containing essentially no covalent bonds, orgrafts between them. True IPNS are also homogeneous mixtures ofcomponent polymers. Further examples of an additional candidatematerials would be a polyurethanepolysiloxane (IPN) bilaminated with apolyparaxylene or alternately bilamination of polydimethylsiloxane(PDMS) and polyparaxylene. Coextruded laminates of this type can beselected according to the desired gas permeability for vapor and O₂, N₂and CO₂ diffusion and their specific selectivity requirements as well asfor direction of gas migration when appropriately layered.

Manufacturers of materials suitable for use in the construction of thedistendable membrane, include Dow Chemical, General Electric, B.P.Polymers, Mobay Chemical, Shell Oil Corp., Petrarch Systems, DuPont,Concept Polymers and Union Carbide Corp.

With respect to the structural cover 34, in certain embodiments of theinvention, this component can be produced from one of several polymergroups. The plastic structure of this component typically contains anintricate network of open celled omni directional pores. The pores canbe made in average sizes for 0.8 micron to 2,000 micron and, gives theporous plastic a unique combination of venting filtering, wicking anddiffusing capability and structural strength. Further, the material isstrong, lightweight, has a high degree of chemical resistance anddepending on the particular configuration of the apparatus, can beflexible. The degree of hardness can range from soft, resilient orrigid, and depending on the specific micro diameter range desired, thefollowing polymers can be employed: Polypropylene(PP), Ultra highmolecular weight polyethylene (UHMW PE), High density polyethylene(HDPE), Polyvinylidene Fluoride (PVDF), Ethylene-vinyl acetate (EVA),Styrene Acrylonitrile (SAN), Polytetrafluoroethylene (PTFF). A suitablesource of these materials is Porex Technologies of Fairburn, Ga.

An alternate material for use in constructing the covers, as forexample, covers 34 and 80, when the cover is to serve as a non-permeablegas barrier, is a material sold by B-P Chemicals International ofCleveland, Ohio, under the name and style "Barex". This material, whichcan also be used to alternately construct base 14 and element 28, is aclear rubber modified Acrylonitrile Copolymer which has wide applicationin the packaging industry because of its superior gas barrier, chemicalresistance and extrusion (thermoforming) and injection moldingcapabilities. Structures using this material can be manufactured ineither monolayer or coextrusion (with such other materials aspolyethylene, polypropylene, polystyrene and other modified styrenes).Combinations of different materials can be used to enhance the desiredphysical properties of the thermoformed part.

Finally, the foam pad adhesive 38 and peel strip 40 is preferablycomposed of a thin (1/32") 30 mil closed cell polyethylene (PE) foamdouble coated with a non-sensitizing acrylic pressure sensitive adhesive(PSA), and 90 lb. white polyethylene coated release liner (peel strip).This foam is also available in 1/16 inch and 1/8 inch thickness. Thefoam is stretchable, soft, elastic, conformable, cushioning,hypoallergenic, and is desirable for application where sustained use isrequired. The material is available from the 3M Company of Saint Paul,Minn. and from Betham Corporation of Middlesex, N.J.

Turning now to FIGS. 10 through 17, another embodiment of the inventionis thereshown. The apparatus of this form of the invention is similar inmany respects to that previously described and like numbers are used toidentify like components. Unlike the apparatus illustrated in FIGS. 1through 9 which has a thermo sealed filling port, the apparatus of thissecond form of the invention is adapted to be filled using a hypodermicsyringe. The device may have a cover made of the same material as cover34, or may have a different type of impermeable cover, the function ofwhich will presently be described.

Referring to FIG. 10, the apparatus can be seen to comprise a base 14, adistendable member 24 and a flow control member 26 all of which are ofthe same general character and function in the same manner as in theearlier described embodiment of the invention. The distendable memberengaging element 60 is of slightly different construction and includesfilling means which enables chamber 25 to be filled using a hypodermicsyringe and needle of the character identified in FIG. 17 by the numeral62. Element 60 is superimposed over flow control member 26 and includesa pair of longitudinally extending, spaced apart upstandingprotuberances 64. Each protuberance 64 is provided with fluidpassageways 66 which communicate with fluid passageways 16 and 18provided in base 14. Element 60 also includes an upstanding transverselyextending portion 68 having a fluid passageway 70 extending therethrough(FIGS. 10, 11 and 17). In this second embodiment of the invention, theopen end 70a of passageway 70 is closed by a septum means for receivinga hypodermic needle. The septum means is here provided as a septum 72which is adapted to sealably close the open end 70a of passageway 70.Septum 70 is constructed of a self-sealing, puncturable material such assilicone-SEBS (a composite incorporating a silicone interpenetratingnetwork (IPN) into a styrene-ethylene butylene-styrene block copolymer).If desired, the earlier form of the apparatus of the invention as shownin FIGS. 1 through 9 can alternatively have a fill means such as shownin FIG. 17 to permit filling in the field. As best seen by referring toFIG. 12, passageway 70 is in communication with a pair of logitudinallyextending passageways 74 formed in element 60. Passageways 74 are, inturn, in communication with chamber 25 via passageways 76.

Cover 80 is formed of a clear plastic material which is impermeable tofluid including gases. This type of cover is used when the medicinalagent within chamber 25 is such that it must be sealed with respect toatmosphere. As best seen in FIG. 18 cover 80 is provided with a pair oflongitudinally extending protuberances 82 which are interconnected by aweb 84. Web 84 carries on its upper surface an impermeable barrier peelstrip 86 that covers vent means provided in web 84 to enable venting ofchamber 25 at time of use.

The apparatus of this second form of the invention includes a needleassembly 42 of similar function and construction as that previouslydescribed and includes a shielded injection needle 46. The needleassembly is provided with web means and a frangible section 42c toenable portion 42b of the needle assembly to be removed in the mannershown in FIG. 16.

As before, so long as needle assembly 42 remains intact in the mannershown in FIG. 12, the fluid will be retained within chamber 25. However,upon twisting off the frangible section 42c so that portion 42b on theneedle assembly can be removed as shown in FIG. 16, distendable membrane24 will begin to expel fluid through the needle 46. The rate ofexpulsion of fluid is, of course, controlled by the permeable membrane26 which is disposed intermediate the fluid flow passageways 66 ofmember 60 and fluid flow passageways 16 and 18 formed in base 14.

Referring to FIGS. 18 through 21, another embodiment of the invention isthereshown. The apparatus of this form of the invention is similar inmany respects to the embodiment shown in FIGS. 1 through 9 and likenumbers are used to identify like components. Unlike the apparatusillustrated in FIGS. 1 through 9, the apparatus of this third form ofthe invention does not embody an injection needle assembly. Rather, thedevice of this embodiment includes a luer connector assembly 90, thefunction of which will presently be described.

Turning particularly to FIG. 18, the apparatus can be seen to comprise abase 14, and an operating assembly 92 associated therewith comprising adistendable member 24, a distendable member engaging element 28, a flowcontrol member 26 and a cover 34, all of which are of the same generalcharacter and function in the same manner as the embodiment of theinvention shown in FIGS. 1 through 9 The device also includes anadhesive foam pad 38 and a peel strip 40 carried by base 14.

The luer connector assembly 90, which comprises the distinguishingfeature of this form of the invention, is integrally formed with base 14and includes a distal portion 90a and a proximal portion 90b. Distalportion 90a is provided with a longitudinally extending bore 94 whichcommunicates with outlet 22 of base 14. Comprising the proximal portion90b of assembly 90 is a luer connector of standard construction having afluid passageway 96 which communicates with bore 94 of distal portion90a. The outlet of passageway 96 is sealed by a frangible closure whichis removable to activate fluid flow. The outboard end of distal portion90a, designated in the drawings as 90c is of reduced diameter and isreadily flexed to permit easy connection of the luer connector "L" withan external system "E" (FIG. 20).

As shown in FIGS. 18 and 21, base 14 includes fluid conduits 16, 18 and20 which communicate with outlet passageway 22. Distendable membrane 24functions to expel fluid from chamber 25, through flow rate controlmember 26 and outwardly through outlet passageway 22 in the mannerpreviously described.

Referring to FIGS. 22 through 29 yet another form of the invention isshown and identified by the numeral 100. For certain medicinal agents,it is desirable to provide an initial high rate delivery followed by aslower rate sustained delivery. This form of the invention permits thisto be accomplished. The apparatus of this form of the invention issimilar in many respects to the embodiment shown in FIGS. 1 through 9and like numbers are used to identify like components. Unlike theapparatus illustrated in FIGS. 1 through 9, the apparatus of this fourthform of the invention is not limited to a fixed rate infusion of themedicinal agent. Rather, because of the novel configuration of thedistendable membrane engaging element and the dual flow rate controlmembers of this form of the invention, a controlled variable rate offluid flow is possible.

As best seen in FIGS. 22, 23 and 24, the apparatus of this last form ofthe invention also comprises a laminate, or layered, structure made upof a plurality of thin plate-like components. The apparatus includes athin, generally planar plate-like base 102, having a transverse recess104 in communication with a fluid outlet passageway 106. A thin,generally planar elastic distendable membrane, or member 108 cooperateswith base 102 to form a pair of discrete chambers 110 and 111 (FIG. 27).For certain applications, Chambers 110 and 111 may be of differentindividual size and configuration each having different volumes. Asbefore, member 108 is distendable out of plane in the manner shown inFIG. 25 by the introduction of fluid into the chambers under pressure.The method of introduction of fluids into chambers 110 and 111 willpresently be described.

Forming an important aspect of the apparatus of this fourth form of theinvention is the provision of flow control means which are disposedinternally of chambers 100 and 111 for controlling the rate of fluidflow of fluid from each chamber through outlet 106. In the embodiment ofthe invention hereshown, the flow control means is provided in the formof a flow rate control assembly 112 which is received within recess 104formed in base 102 in the manner shown in FIGS. 22 and 24. Flow ratecontrol assembly 112 includes a pair of permeable members 114 and 116which, as will presently be described, precisely control the rate offluid flow from chambers 110 and 111 into fluid outlet 106. Passageway106 is in communication with the fluid passageway of needle assembly 42which is of the same construction as previously described herein.

As best seen in FIG. 24, assembly 112 comprises a manifold member 118which is closely receivable within recess 104 formed in base 102. Member118 is provided with an internal fluid conduit 120 having fluid inlets122 and 124 at either end and a fluid outlet 126 proximate its center.Outlet 126 is adapted to communicate with outlet passageway 106 providedin base 102 when member 118 is in position within recess 104. Permeablemembers 114 and 116 overlay inlets 122 and 124 and, in a mannerpresently described, control the flow of fluid into these outlets fromchambers 110 and 111. Fluid inlets 122 and 124, can be constructed invarious geometries and, in cooperation with the ullage means, presentlyto be described, to provide various degrees of active surface area ofthe rate control membrane.

The distendable member engaging element 130 of this latter form of theinvention is of slightly different construction and includes fillingmeans which enable chambers 110 and 111 to be filled separately. As bestseen in FIGS. 22 and 25, element 130 is superimposed over base 102 andflow control assembly 112 and includes a pair of longitudinallyextending, spaced apart upstanding protuberances 132 and 134.Protuberances 132 and 134 are provided with fluid passageways 136 and138 respectively. Passageway 136 communicates with fluid inlet 122 andpassageway 138 communicates with inlet 124 of assembly 112. By varyingthe configuration of these passageways and fluid inlets alternate activesurface areas of the flow control membrane can be exposed. Element 130also includes an upstanding transversely extending portion 140 having apair of fluid passageways 142 and 144 extending from the open ends 142aand 144a thereof. As shown in FIG. 23, passageway 142 is incommunication with passageway 136 of element 130 via a passageway 152and passageway 144 is in communication with passageway 138 of element130 via a passageway 148. Passageways 146 and 148, in turn, communicatewith chambers 110 and 111, respectively, via passageways 150 and 152respectively (see FIGS. 25 and 26). Open ends 142a and 144a ofpassageways 142 and 144 are closed by any suitable means such as heatsealing.

The apparatus of this fourth embodiment of the invention is adapted tobe filled with the selected medicinal fluid at time of manufacture. Thisis accomplished by forcing fluid under pressure into passageways 142 and144, and thence, into chambers 110 and 111 via passageways 150 and 152.As the fluid under pressure flows into the two chambers, it will causethe membrane 108 to distend upwardly into engagement with cover 34 inthe manner shown in FIG. 27. After chambers 110 and 111 have been filledwith the selected medicinal fluid, passageways 142 and 144 are sealablyclosed. Cosmetic closure plugs 154 and 156 can be used if desired at theends of conduits 142 and 144. It is to be observed that membrane 108 isbonded along its margins 108a to member 130 and is in sealableengagement along its longitudinal center line with member 130intermediate protuberances 132 and 134. With this construction, chambers110 and 111 are maintained independent from one another.

Upon twisting off the frangible section 42c so that portion 42b on theneedle assembly can be removed as shown in FIG. 29, elastic distendablemembrane 108 will begin to expel fluid through flow control members 114and 116. The rate of flow of fluid is, of course, controlled by thedegree of permeability of each of the members 114 and 116. If one ofthese members has a greater permeability than the other, fluid will flowthrough that member at a greater rate. Accordingly, by varying thepermeability of members 114 and 116, and with the output summed via flowchannels 120 and 106, a larger initial volume of fluid can be injectedinto the patient. Continuous injection of fluid at a slower controlledrate will then follow. For example, if member 114 has a high degree ofpermeability, fluid will be forced out of chamber 110 at a rapid rate.On the other hand, if member 116 has a low permeability, fluid will beforced out of chamber 111 at a slower rate. With this arrangement, fluidcan be simultaneously injected initially at a high rate from chambers110 and 111 then at a much slower rate from chamber 111.

As indicated in FIG. 22, the apparatus is closed by a cover 34 having amedicant label 36. If a barrier cover and base configuration is used,cover vent means as previously described, must be provided. Affixed tothe bottom of the base is an adhesive foam pad 38 and a peel strip 40 sothat the apparatus can be self-attached to the patient.

Turning now to FIGS. 30, 31, and 32, another embodiment of the apparatusfor use in infusing medicinal fluids into a patient is there illustratedand generally designated by the numeral 200. The device of this form ofthe invention is similar in many respects to that shown in FIGS. 18through 21 and like numbers are used to identify like components. Asbest seen by referring to FIG. 30, the apparatus comprises a thin,generally planar plate-like base 202 having at least one flow ratecontrol channel. In the form of the invention shown in FIGS. 30 and 30A,the base is shown as having a pair of flow rate control channelsprovided here as longitudinally extending fluid conduits 204 and 206.Conduits 204 and 206 are interconnected by a fluid transfer manifold, ortransverse conduit 208, which, in turn, is interconnected with a fluidoutlet passageway. Distendable membrane engagement means, shown here asprotuberances 209, perform the same function as protuberances 30previously described. It is to be understood that in some applicationsonly a single protuberance is provided and in other applications noprotuberance at all is required.

A thin, initially generally planar distendable elastomeric membrane, ormember, 24 (FIG. 32) cooperates with base 202 to form a chamber 25 (FIG.32). Member 24 is distendable in the manner shown in FIG. 32 by theintroduction of fluid into the chamber under pressure. As previouslydescribed herein, as the distendable member 24 is distended by the fluidpressure, internal stresses are formed in the member which continuouslyurge it toward engagement with protuberances 209 as it trys to return toits original configuration. The method of introduction of fluids intochamber 25 is as previously described in connection with the embodimentof FIGS. 12 through 21.

An important feature of this latter embodiment of the invention is theprovision of a multiplicity of flow rate control micro-channels 210 inbase 202. Micro-channels 210 are disposed on either side of conduits 204and 206 and communicate therewith via flow control means of a characterpresently to be described.

In the embodiment of the invention shown in FIGS. 30 through 32, theflow control means is provided in the form of a thin, multilayered orgradiated assembly 212 which is superimposed over channels 210 in themanner shown in FIG. 32. With this construction, when the device is in afluid discharge mode, fluid within chamber 25 is forced by membrane 24through channels 213 provided in protuberances 30, through assembly 212,through micro-channels 210, into conduits 204 and 206 and outwardlythrough outlet passageway 214. Passageway 214 is connected withdispensing means shown here as luer connection assembly 90 whichincludes a fluid flow conduit and fluid dispensing port or luerconnector "L". By controlling the area of the micro-channels, the activesurface area of membrane assembly 212 which is exposed to fluid can bevaried in a manner to optimize fluid flow through assembly 212.Similarly by controlling the size and shape of the micro-channels, therate of flow of the fluid through membrane assembly 212 can also beuniformly maintained.

As indicated in FIG. 31, the flow control means of this form of theinvention, rather than consisting of a single layer of a permiablematerial having the desired fluid flow characteristics, here comprisesan assemblage of a plurality of layers of permiable materials, P-1, P-2,and P-3, each having selected characteristics. These layers, which maybe composites, thin films, or porous substrates, may be constructed ofany of the materials previously described herein so that the fluidpressure flow characteristics of the assemblage can be optimized for theparticular medicinal or other fluid being dispensed. For example, layerP-1 may comprise an asymmetric membrane, or film, having a firstporosity, P-2 may comprise a resin membrane or film having a secondporosity and layer P-3 may comprise a carrier substrate of predeterminedporosity. In another application P-1 and P-3 may take the form ofcarrier substrates and P-2 may comprise a very thin, rate controlelement. In this way a unique composite, sandwich-like assemblage can beconstructed. In certain applications assembly 212 can be constructedwith gradient layers rather than with discrete elements in a manner toproduce comparable results.

The multilayered, or gradient layer construction described in thepreceding paragraph permits easier, thin-film manufacture, precise flowcontrol over extended periods and easier handling of the membrane filmduring system manufacture.

Referring next to FIGS. 33 through 39, still another embodiment of thepresent invention is there shown. This embodiment of the invention isalso similar to that shown in FIGS. 18 through 21 and like numerals areused to identify like components. As best seen in FIG. 33, the devicecomprises a base 300 having a pair of flow rate control channels 302 and304 and a transversely extending fluid transfer manifold conduit 306.Conduit 306 is connected with an outlet 300 (FIG. 34) which, in turn, isin communication with a fluid dispensing means, shown here as a fluiddispensing port 312.

Unlike the embodiments of the invention previously described, the deviceof this form of the invention does not include a flow rate controlmembrane of the character previously described. Rather, the rate offluid flowing from the dispensing means of the device is controlled byflow control means disposed intermediate outlet 310 and fluid dispensingport 312. The flow rate control means is here provided as a fluid flowmicro-conduit 314 and a porous member 316 (FIG. 36) which functions torestrict the flow of fluid between outlet 310 and dispensing port 312.

Another critical difference between the embodiment of the invention nowbeing considered and the previously described embodiments resides in theunique character of the stored energy means used for discharging fluidfrom the device. Here the stored energy means, rather than being asingle isotropic, elastomeric distendable membrane, comprises a laminateassemblage made up of a plurality of initially generally planardistendable elements or films. Referring particularly to FIG. 39, thestored energy means is there shown as a laminate assemblage 318 made upof individual elements or membranes 320, 322, 324, 326 and 328.Assemblage 318 functions in much the same way as the earlier describeddistendable membranes, and uniformly cooperates with base 300 to definefluid chambers or reservoirs 25. However, by constructing the storedenergy means from a composite of several distinct elements or layers,the elastic characteristics of the stored energy means can be preciselytailored and the stored energy means can be uniquely constructed tofunction also as a gas permeability valve as well as the means forexpelling fluids from the fluid reservoir. This unique, multilayered orgradient construction permits venting to atmosphere through the membranesurface certain selected, entrained gases or vapors in the reservoirwhile simultaneously precluding any negative migration of selectedatmospheric gases or vapors into the reservior. Where the composite ismade up of two or more layers of alternating thickness and premeability,and the permeability constants of the individual film layers arepressure dependent, the permeability of the stored energy means iseffected and the direction of flow of the permiant through the membranewall is controlled by the order in which the individual layers orgradiations of the composite are assembled.

For example, referring to FIG. 39, layer 320 which may be distal to thereservoir comprises a thin film elastomer of a first thickness and afirst permeability. On the other hand, layer 328, which may be proximalto the reservoir, comprises a thin elastomer film of a second thicknessand a second permeability. Layers 322, 324 and 326 may be of furtheralternating thickness and permeability and, if desired, may also havedifferent perm-select characteristics. The selective arrangement of thedifferent films each with its own individual permeability constants inascending order, will dictate the direction of flow of selected gasesand vapors through the stored energy means.

Turning now to FIGS. 40 through 45, another embodiment of the apparatusfor use in infusing beneficial agents into a patient is thereillustrated. The device of this form of the invention is unique in thatit provides the opportunity to add to the diluent or other parenteralfluid being introduced into the device selected elements, chemicalcompounds and biologically active materials such as drugs, medicaments,biological agents, or other therapeutic agents (additives). Thisaddition is accomplished by removably affixing the selected additives tovarious forms of support structures which can be placed within the pathof the fluid flowing through the device so that upon contact with thefluid, the additives are released at a controlled rate to the fluid. Inthis way, the delivery system of the invention can be safely renderedtherapeutically active upon hydration of the additive with a selectedparenteral fluid such as a sterile diluent or other acquous solvent.

The basic structure of the device of this new form of the invention issimilar in many respects to that shown in FIGS. 18 through 21 and inFIGS. 33 through 39 and like numbers are used to identify likecomponents.

As best seen by referring to FIG. 41, the apparatus comprises a basemade up of a first, generally planar member 400 and a second companionmember 401 which includes a pair of longitudinally extending flow ratecontrol conduits or channels 402 and 404 which communicate with atransversely extending fluid transfer manifold conduit 406 (FIG. 40).Conduit 406 is, in turn, connected with a fluid outlet 408 which is incommunication with a fluid dispensing means shown here as including afluid dispensing port 410.

First base member 400 is also provided with a pair of longidutinallyextending manifolds 411 which communicate with micro-channels 412 (FIG.44). As best seen in FIG. 42, manifolds 411 and micro-channels 412communicate with conduits 402 and 404 via flow control means of thegeneral character described in connection with the embodiment of theinvention shown in FIGS. 30 through 32. More particularly, the flowcontrol means is here provided as a thin, multilayered or gradiatedassembly 212 (see FIG. 31) which is superimposed over manifolds 411 andmicro-channels 412 in the manner shown in FIG. 41. Assembly 212comprises an upper microporous layer, an intermediate rate controlmembrane and a lower support layer. With this construction, when thedevice is in a fluid discharge mode, fluid which is contained withinchamber 25 (FIG. 44), such as a diluent containing the additive (thebeneficial agent) is initially forced by the stored energy means throughchannels 414 provided in a pair of upstanding protuberances 416 formedon base member 401. As the liquid passes through channels 414, it entersa pair of longitudinally extending manifolds 417 which are formed inbase member 401 and which align with manifolds 411 formed in base member400. Manifolds 417 function to uniquely distribute the fluid as it flowstoward the flow control assembly 212 in a manner to disperse the fluidthroughout a wide area of the flow control assembly. The uppermost layerof the assembly is designed to permit multi-axial flow distributionthereby effectively utilizing an extensive surface area of the ratecontrol membrane. The beneficial agent flows through the rate controlmembrane layer, through the support layer, through micro-channels 412,and thence outwardly through outlet passageway 408. Passageway 408 inturn communicates with dispensing means, shown here as including aconnector assembly 90.

As previously discussed, by controlling the area of the manifolds, thecharacter of the uppermost layer of the flow control means, and the areaof the micro-channels, the active surface area of the rate controlmembrane which is exposed to fluid can be precisely varied in a mannerto predictably achieve the desired fluid flow control. Certain regimesof the various layers of assembly 212 can be rendered hydrophillic orhydrophobic by the appropriate use of materials and coatings in a mannerand in amounts well known in the art. In this way, the wettability ofthe assembly can be precisely tailored as well as the initial gasventing capability of the system.

The distendable membrane engagement means, shown here as protuberances416 (FIG. 41) perform the same function as previously described. It isto be understood that in some applications only a single protuberance isprovided and in other applications no protuberance at all is required.

The stored energy means of this embodiment is of the same character asshown in FIG. 39 and comprises a laminate assemblage 318 made up ofindividual elements or membranes 320, 322, 324, 326 and 328. Assemblage318 functions in much the same way as the earlier described, singlelayer distendable membranes, and uniformly cooperates with base member401 to define fluid chambers or reservoirs 25 (FIG. 44). However, aspreviously mentioned, by constructing the stored energy means from acomposite of several distinct members or layers, the elasticcharacteristics and the resultant energy flux of the stored energy meanscan be precisely tailored. In this way, the stored energy means can alsobe uniquely constructed to function as a gas permeability valve (forexample to prevent external negative migration of fluids into thereservoir) as well as the means for expelling fluids from the fluidreservoir.

As indicated in FIG. 41, superimposed over the base and the storedenergy source is a structural cover 34 of the character previouslydescribed having appropriate medicant and use labels 36. Affixed to thebottom of base member 400 is a cushioning means or pad 38 havingadhesive on both sides. A peel strip 40 is connected to the lowersurface of pad 38. For certain applications, a thin protective film maybe affixed over cover 34 to prevent ingress of liquids or othercontaminants into the device.

Like the apparatus shown in FIG. 10, the present embodiment includesfilling means which enables chambers 25 to be filled with a selectedparenteral liquid using a hypodermic syringe and needle of the characteridentified in FIG. 17 by the numeral 62 (see also FIG. 43). Toaccomplish filling of the chambers, base member 401 includes anupstanding transversely extending portion 418 having a fluid passageway420 extending therethrough. In this embodiment of the invention, theopen end 420a of passageway 420 is closed by a septum means for sealablyreceiving a piercing element such as a hypodermic needle. The septummeans is here provided as a needle septum 422 which is adapted tosealably close the open end 420a of passageway 420. Septum 422 ispreferably constructed of a self-sealing, noncoring, puncturablematerial such as silicone-SEBS. It should also be understood that theseptum means can also take the form of a split septum for use with astate-of-the-art blunt cannula injector system. As best seen byreferring to FIG. 40, passageway 420 is in communication withlongitudinally extending channels 402 and 404. As before, channels 402and 404 are, in turn, in communication with chambers 25. With thisconstruction, an appropriate injectable such as a diluent or parenteralfluid contained within syringe 62 can be introduced into chambers 25 viapassageway 420.

Before considering the highly important adding means of this latestembodiment of the invention a brief introductory background is perhapshelpful.

In the past it has been common practice to mix various types ofseparately packaged drugs with a suitable diluent immediately beforethey are delivered intravenously to a patent. Typically the drugs arepackaged separately from the diluent for various reasons. For example,many drugs do not retain their chemical and physical stability whenmixed with a diluent and thus cannot be stored for any substantialperiod of time. Also, drugs are often packaged separately from thediluent because many firms which manufacture drugs are not engaged inthe business of providing medical solutions in containers forintravenous delivery and vice versa.

Traditionally, the mixing of the drug and the diluent was accomplishedby a doctor, nurse or medical professional injecting the injectablefluid into a glass vial containing the drug. After mixing of the drugand the diluent, the solution thus formed is withdrawn into a syringebarrel and in some instances injected immediately into the intravenoussystem of a patient. More typically however, the reconstituted drug isinjected from the syringe into a larger container of solution forconnection to an intravenous administration set. This prior artprocedure is time consuming, imprecise and generally undesirable.

The device of this latest form of the invention elegantly overcomes thedrawbacks of the prior art reconstituting and delivery techniques byproviding in conjunction with the basic fluid delivery device of theinvention a simple and precise means for automatically mixing thedesired drug with the appropriate diluent at the time the device ischarged.

In the paragraphs which follow, wherein the details of this uniquereconstitution process will be discussed, the following terms will havethe following meanings:

Element--any of the fundamental substances that consist of atoms of onlyone kind and that singly or in combination constitute all matter.

Additive--the element, compound, substance, agent, biologically activematerial, or other material which is to be added, all or in part, to thefluid introduced into the device of the invention.

Polymer--a chemical compound or mixture of compounds formed bypolymerization and consisting essentially of repeating structural units.

Parenteral Fluid--any solution which may be delivered to a patient otherthan by way of the intestines, including water, saline solutions,alkalizing solutions, dextrose solutions acidifying solutions,electrolyte solutions, reagents, solvents and like acquous solutions.

Beneficial Agents--any drug, medicament, pharmaceutical, medicalpolymer, enzyme, hormone, antibody, element, chemical compound or othermaterial useful in the diagnosis, cure, mitigation, treatment orprevention of disease and for the maintenance of the good health of thepatient.

Biologically Active Material--a substance which is biochemically,Immunochemically, physiologically, or pharmaceutically active orreactive. Biologically active material includes at least one or more ofthe following: biochemical compounds (such as amino acids,carbohydrates, lipids, nucleic acids, proteins, and other biochemicalsand substances which may complex or interact with biochemicalcompounds), such biochemical compounds biologically functioning asantibodies, antigenic substances, enzymes, co-factors, inhibitors,lectins, hormones, hormone producing cells, receptors, coagulationfactors, growth enhancers, histones, peptides, vitamins, drugs, cellsurface markers and toxins, among others known to those skilled in theart. Of the group of biologically active materials described, proteinsare of utmost current interest because of the large molecule geneticallyengineered biopharmaceuticals as those species to be immobilized andcongregated on the additive carriers hereinafter to be described. Adiscussion of the use of biomosaic polymers as carriers for biologicallyactive materials is set forth in European Patent Application 0,430,517A2.

Adding Means--an additive and any means for presenting the additive tothe fluid flowing through the fluid passageways of the fluid deliverydevice of the invention in a manner such that all or any part of theadditive will be added to the fluid. The adding means comprises theadditive and the additive presentation means which may take the form ofa functional support, or carrier, an anchorage, a deposition or reactionsite or an element holder with or without some type of intermediatematrix or other release composition.

Additive Presentation Means--Any means such as a functional support orsubstrate for presenting the additive to the fluid flowing through thedevice. The functional substrate can comprise a polymer, copolymer, aninter-polymer, a ceramic, a crystal sponge, a carbon based matrix, acelullosic, glass, plastic, biomosaic polymers, azlactone-functionalpolymer beads, adduct beads, carboxylate-functional polymer beads, gums,gells, filaments and like carriers.

By way of illustration, the adding means of the invention can takeseveral different forms such as those illustrated in FIGS. 43 and 45.However, in its preferred form, the adding means includes acylindrically shaped, functional support structure which is insertedinto passageway 420 and to which various additives, including beneficialagents such as drugs, biologically active materials, and chemicalelements and compounds can be releasably connected. These additives arecarried by the structure in a manner such that, as the liquid flowsthrough passageway 420 and circulates through the support assembly inthe manner shown by the arrows in FIG. 43, the additives will bepresented to the liquid flow and efficiently added to the liquid as itflows toward chambers 25.

The additives themselves can also take various physical forms includingliquid, solid, granular, powder, particle, gel, wax, hydrocolloidcarrier, a gum, film, tablet, crystalline, emulsions, microcrystalline,microspherical, spray dried compounds and lypohilized compounds andsaturants. The additives can be removably connected to, immobilized on,impregnated within or supported by the support means in a number ofways. The additives can be chemically or mechanically attached, affixed,or bound directly or indirectly, linked or cross linked, anchored to thesurfaces of the support, or surface active agent or they can beabsorbed, reaction catalyzed, electrostatically encapsulated, attachedby chemical modification or transformation to the carrier surface,polymerized on or through the carrier, with or without the use of aninterpolymer, localized, entrapped, suspended, deposited, impregnated,coated, or occluded or otherwise removably affixed within voids, cells,tubules, and intersticies formed in the support. One important methodfor removably affixing the additive to the functional support meansincludes treating the functional support means with a compound havingselected reactive functional groups such as azlactone functionalcompounds with their unique ability to react with aqueous media andtheir high binding capacity. In this way complexing agents, catalystsand biological materials such enzymes or other proteins, as well asbiomacromolecules can be attached to the carrier for later removal andrecovering. Additionally, the use of one or more monomeric orpolymerized surface active agents allows for rapid dissolution andsmooth liberation of the additives. A discussion of such surface activeagents is contained in U.S. Pat. No. 4,963,367 issued to Ecanow.

Similarly, the additives can be added to or intermixed with the liquidflowing through the device by one or more of various mechanisms,including mechanical release, chemical reaction, dissolution,disorbsion, debinding, delinking, bioseparation, diffusion, washing,disintegration, errosion, dissassociation, solubilization, leeching,enzymatic cleavage, biological reaction, osmosis, separation from ringopening materials by a ring opening reaction, and other separationmeans.

Additionally, a polymer can be used as the carrier or support for somecomponent of a reaction system. Three classes of polymeric supports canbe used, namely polymeric reagents, polymeric catalysts and polymericsubstrates. A discussion of polymers as carriers or supports iscontained in Principles of Polymerization, Second Edition by GeorgeOdian. Microporous polymers usable as carriers are also fully describedin U.S. Pat. No. 4,519,909 issued to Castro.

Turning now to FIGS. 41 and 43, one form of adding means, or combinationadditive carrier and additive is there illustrated and generallydesignated by the numeral 423. This form of the adding means comprises agenerally cylindrically shaped assembly including a substantiallycylindrical, porous substrate 423a into which an injector inlet tube423b is closely received. Surrounding porous substrate 423a is a sleeve423c having a multiplicity of flow channels 423d. As shown in FIG. 43,the assembly thus formed is inserted into fluid passageway 420 formed intransversely extending portion 418. Receivable within the inlet openingof tube 423b is the previously identified needle septum injection site422. Connected to portion 418, as by bonding is an insert 424 (FIG. 41)which functions to contain the septum within the device.

In using the apparatus of the embodiment of the invention shown in FIGS.40-44, septum injection site 422 is penetrated by needle 62 and thesterile diluent is introduced into inlet passageway 420 using the needlesyringe. As indicated by the arrows in FIG. 43, as the diluent flowslongitudinally of inlet passageway 420 it will pass through porousmember 423a, into flow channels 423d and then into chambers 25 urgingthe distendable membrane 318 outwardly into the position shown in FIGS.42 and 44. As the liquid flows through porous member 423a, the additivespresented to the liquid will be added to the flow, or solubilized by thediluent, thereby activating the diluent to form the therapeutic solutionto be dispensed to the patient.

The liquid, such as a parenteral fluid, which is introduced intopassageway 418 can include, by way of example, a reagent, a sterilediluent, various electrolytes, aqueous solutions such as aqueoussolutions of dextrose, saline solutions, alkalinizing solutions,acidifying solutions, polyonic solutions and any other liquids that canserve as a vehicle for the administration of therapeutic or beneficialagents which are desirable to administer to the patient by infusion.

Turning now to FIG. 45, various other forms of adding means are thereillustrated. For example, numeral 425 identifies an assembly comprisinga porous substrate with interconnecting voids, such as a crystal sponge425a, over which various outer coatings 425b exhibiting one or moreadditives are laminated. The selected additives such as elements,chemical compounds, drugs and functional intermediates are provided onor within the coating layers by techniques well known to those skilledin the art. The additives exhibited by the layers are, of course,introduced into the sterile diluent as the diluent flows along of theinlet passageway 420. In this instance, since the substrate will not bedamaged by the needle 62, as might a polymer or celullosic carrier, useof the injector inlet tube 423b is not required.

Another form of additive assembly designated in FIG. 45 by the numeral427, comprises a solid tubular member having an internal, axiallyextending fluid passageway 427a, the inner wall of which is lined with aseparation coating affixing the additives such as chemical compounds andbeneficial agents, or medicaments.

Still another form of additive assembly is identified in FIG. 45 by thenumeral 429. This assembly comprises a cylindrical, porous plug likemember made up of a multiplicity of fused together microspheres or beads429a, each of which is coated with a separation or reactive coating uponwhich is deposited an additive such as a biologically active material orother beneficial agent. The microspheres can be formed of glass, plasticor other suitable materials.

The numeral 431 of FIG. 45 identifies yet another form of the addingmeans of the invention. In this form of the invention a generallycylindrically shaped functional support means for affinity attachment,and subsequent release of the additive, is formed from a multiplicity ofmicroporous polymers 431a presenting a multiplicity of reactive sitesover a wide area for species immobilization. In this form of theinvention, in order to avoid needle damage to the polymers, it isnecessary to use an injector inlet tube of the character shown in FIG.41 and identified by the numeral 423b.

The additive assembly designated in FIG. 45 by the numeral 433 may alsorequire the use of an injector tube. This assembly is made up of highporosity, semi-sythetic celullosics 433a formed into a generallycylindrical shape and having interconnecting, interstial surfaces orfunctional support means and is similar in size and configuration toactivating assembly 423.

Another slightly more complex additive assembly is identified by thenumeral 435. This assembly is made up of a plurality of spaced apart,porous disk shaped wafers 435a, 435b, 435c, and 435d each wafer being ofthe same or different construction and porosity and each having reactivesites presenting to the liquid flow specially selected additives such asbeneficial agents, elements or compounds so that multiple reactivitiesand selectivities can be achieved. With this construction, a widevariety of liquid flow rates, and complex sequential separations andpriority staged substance introduction into the system reservior can beachieved by specially designing each of the wafers that cooperate tomake up the structural support.

Still another form of activating assembly is designated in FIG. 45 bythe numeral 437. This assembly comprises a cylindrically shaped porousstructure 437a which is provided with pores of varing sizes only some ofwhich are coated, pluged or impregnated with selected additives 437band, as necessary, functional intermediate materials.

Finally, the functional support member identified by the numeral 439exemplifies yet another form of adding means of the invention. Thismember, which is also of a generally cylindrically shaped configuration,is constructed from a porous ceramic material into which selectedadditives and intermediate compounds have been removably affixed. Member439, being made of a hard ceramic, would not be easily damaged by theneedle 62 and therefore the injector inlet tube is generally not needed.Member 439 can also be constructed from fuzed activated carbonparticles, coated porous zirconium oxide bonded spherules, or otherporous forms of polymer reactive supports including joinedazlatone-functional polymer beads suitable for the attachment offunctional materials.

Assemblies 423 through 439 which may be soluble or insoluble areintended to merely exemplify, not to limit, the wide variety ofmaterials and constructions that can be used to introduce the desiredadditives into the liquid flow introduced into the inlet flow passageway420 of the device.

Turning now to FIG. 46, another form of the invention is shown. Thisfigure shows in cross-section one set of the manifolds 411 and 417 whichare formed in base members 400 and 401 of the device. In certainapplications, it is sometimes advantageous to provide liquiddistribution means within manifolds 411 and 417 to enhance the uniformflow of liquid through the manifolds. In the embodiment of the inventionshown in FIG. 46, the liquid distribution means is provided as generallyplanar strips of felt-like hydrophillic polymer material 440 which isreadily wetted by the solution being expelled from chambers 25 by thestored energy means, or distendable membrane 318. Material 440 can be ofany type that will enhance the uniform flow of the solution containedwithin chambers 25 and can include ceramic, crystalline, polymer, spongeand other similar materials which have hydrophillic characteristics.

Turning to FIG. 47, another embodiment of the apparatus for use ininfusing beneficial agents into a patient is there illustrated. Thebasic structure of the device of this latest form of the invention issimilar in many respects to that shown in FIG. 41 and like numbers areused to identify like components. The major difference between thedevice shown in FIG. 47 and that shown in FIG. 41 is that the transversefilling portion 418 is replaced by a longitudinally extending fillingportion 518. As will be discussed in greater detail hereinafter, theadding means including the additive carriers of this form of theinvention are also of a somewhat different configuration.

As in the apparatus of FIG. 41, the apparatus here comprises a base madeup of a first, generally planar member 500 and a second companion member501 which includes a pair of longitudinally extending flow rate controlconduits or channels 502 and 504 which communicate with a fluid outlet508 which is in communication with a fluid dispensing means shown hereas including a fluid dispensing port 510.

First base member 500 is also provided with a pair of longidutinallyextending manifolds 511 which communicate with micro-channels of thecharacter shown in FIG. 44 and identified by the numeral 412. Manifolds512 as well as the micro-channels communicate with conduits 502 and 504via flow control means. The flow control means is here provided as athin, multilayered or gradiated assembly 512 which is superimposed overmanifolds 511 in the manner indicated in FIG. 47. Assembly 512 comprisesan upper microporous substrate 512a, an intermediate rate controlmembrane 512c and a lower support substrate 512d. With thisconstruction, when the device is in a fluid discharge mode, fluid whichis contained within chamber 25 (FIG. 44), such as a diluent containingthe additive (the beneficial agent) is initially forced by the storedenergy means through channels 514 provided in a pair of upstandingprotuberances 516 formed on base member 501.

As previously discussed, by controlling the area of the manifolds, thecharacter of the uppermost layers of the flow control means, and thearea of the micro-channels, the active surface area of the rate controlmembrane which is exposed to fluid can be precisely varied in a mannerto predictably achieve the desired fluid flow rate control. As before,certain regimes of the various layers of assembly 512 can be renderedhydrophillc or hydrophobic by the appropriate use of materials andcoatings in a manner, amount, area and location well known in the art.In this way, the wettability of the assembly can be precisely tailoredas well as the initial gas venting capability of the system.

The distendable membrane engagement means, shown here as protuberances516 perform the same function as previously described. It is to beunderstood that in some applications only a single protuberance isprovided and in other applications no protuberance at all is required.

The stored energy means of this embodiment is also of the same generalcharacter as previously described and comprises a laminate assemblage518 made up of individual elements or membranes 540, 542, and 544.Assemblage 518 functions in much the same way as the earlier described,single layer distendable membranes, and uniformly cooperates with basemember 501 to define fluid chambers or reservoirs 25 (FIG. 44). However,as previously mentioned, by constructing the stored energy means from acomposite of several distinct members or layers, the elasticcharacteristics and the resultant energy flux of the stored energy meanscan be precisely tailored. As before, the stored energy means can alsobe uniquely constructed to function as a gas permeability valve tocontrol gas flow in one direction as well as the means for expellingfluids from the fluid reservoir.

As indicated in FIG. 47, superimposed over the base and the storedenergy source is a cover 34 which includes a porous structural member34a and a film cover 34b. Appropriate medicant primary labels andinstruction for use labels 36 are affixed to cover 34. Affixed to thebottom of base member 500 is a cushioning means or pad 38 havingadhesive on both sides. A peel strip 40 is connected to the lowersurface of pad 38.

Like the apparatus shown in FIG. 10, the present embodiment includesfilling means which enables chambers 25 to be filled with a selectedinjectable such as a parenteral liquid using a hypodermic syringe andneedle of the character identified in FIG. 17 by the numeral 62 (seealso FIG. 43). To accomplish filling of the chambers, base member 501includes the previously mentioned upstanding longitudinally extendingportion 519 having a fluid passageway 520 extending therethrough. Inthis latest embodiment of the invention, the open end of the passagewayis closed by a septum means for sealably receiving a piercing elementsuch as a hypodermic needle. The septum means is here provided as aneedle septum 522 which is adapted to sealably close the open end ofpassageway 520. Passageway 520 is in communication with the fluidchambers 25 so that an appropriate parenteral fluid contained withinsyringe 62 can be introduced into chambers 25 via passageway 520.

One form of adding means and additive carrier of this latest embodimentis generally designated in FIG. 47 by the numeral 523. This form of theadding means comprises an elongated, generally cylindrically shapedassembly including a substantially cylindrical, porous substrate 523ainto which an injector inlet tube 523b is closely received. The assemblycomprising substrate 523 and injector inlet tube 523b is closelyreceivable within longtudinally extending fluid passageway 520 formed inlongitudinally extending portion 519. Receivable within the inletopening of tube 523b is the previously identified needle septum 522which is held in position by insert 524 which is bonded to base member50.

Disposed intermediate septum 522 and injector inlet tube 523b is aporous flow restrictor 525 which controllably resists the fluid which isflowing into the injector tube. This resistor can be constructed fromany suitable porous inert material such as a ceramic or plastic whichresists fluid flow in a manner to controllably regulate the residencetime of the fluid being introduced into the carrier 523.

As was the case with the embodiment of the invention shown in FIGS. 40through 45, various additives, including beneficial agents such asdrugs, biologically active materials, and chemical elements andcompounds can be releasably connected to additive carrier 523. Theseadditives are carried by the structure in a manner such that, as theliquid flows through passageway 520, the additives will be presented tothe liquid flow, separated and released and efficiently added to theliquid as it flows toward the reservoir chambers 25.

As before, the additives can take the various physical forms previouslydescribed herein and can be removably or releasably connected to thecarrier in the many ways previously described. Similarly, the additivecan be added to the fluid introduced into the device by the variouschemical and mechanical means previously described for easy removal andrecovery.

Various other forms of adding means and additive assemblies of thecharacter illustrated in FIG. 45 can also be used with this latestembodiment. For example, a porous substrate with interconnecting voids,such as a crystal sponge 425a over which various outer coatings 425b ofone or more additives are laminated can be used. Similarly, a solidtubular member such as member 427 (FIG. 45) having an internal, axiallyextending fluid passageway 427a, the inner wall of which is lined with aseparation coating or surface active agent or intermediate matrixaffixing the additives such as medicaments, drugs and other beneficialagents can be used.

Still another form of additive assembly which can be used is of thecharacter identified in FIG. 45 by the numeral 429. This assemblycomprises a cylindrical member made up of a multiplicity of fusedtogether microspheres 429a, each of which is coated with a surfaceactive agent separation coating upon which is deposited and chemicallyanchored a biologically active material or other beneficial agent. Otherforms of the additive means which can be used include those shown inFIG. 45 and identified by the numerals 431, 433, 435, 437 and 439.

In certain applications the additive, as defined herein, can bedeposited, coated or otherwise removably affixed interstitially of oronto a surface of the membrane 544 of the stored energy means which isexposed to the liquid. With this construction, the fluid enteringchambers 25 will be exposed to the additive and the additive will beadded to the fluid prior to its infusion into the patient.

Additionally in some applications, the additive can be removably affixedto, impregnated within or otherwise anchored directly or indirectly onor within either or both of the base members 500 and 501. In this way,the additive can be separated from the base members and added to theliquid which contacts the base members at any time prior to its infusioninto the patient.

In other applications, the additive can be deposited, coated orotherwise removably affixed interstitially of or onto the rate controlassembly 512 so that the additive is exposed to the fluids flowingthrough the rate control assembly in a direction toward the outlet ofthe device.

Referring to FIGS. 48 through 60, another embodiment of the apparatusfor use in infusing beneficial agents into a patient is thereillustrated. The device of this form of the invention is similar in manyrespects to the embodiment shown in FIGS. 40 through 45 in that itprovides the opportunity to add to the diluent or other parenteral fluidbeing introduced into the device selected elements, chemical compoundsand biologically active materials such as drugs, medicaments, biologicalagents, or other therapeutic agents (additives). However, in this latestform of the invention selected additives are removably affixed tovarious forms of support structures which are, in turn, contained withina novel additive subassembly that can be inserted into the device in amanner to place the additives within the path of the fluid flowingthrough the device. In this way the additives, such as drugs, can remainsealed in the prepackaged additive subassembly, which preferablycomprises a glass vial, until such time as the subassembly isinterconnected with the base of the apparatus and diluent flow throughthe subassembly is commenced.

Because the basic structure of the device in this latest form of theinvention is similar in many respects to that shown in FIGS. 18 through21, FIGS. 33 through 39 and FIGS. 48 through 54, like numbers are usedto identify like components.

As best seen by referring to FIG. 48, the apparatus comprises a basemade up of a first, generally planar member 600 and a second companionmember 601. Member 600 includes a pair of a longitudinally extendingfluid flow manifolds 602 and 604 which communicate with a transverselyextending fluid transfer passageway 606 (FIG. 48). Passageway 606 is, inturn, connected with a fluid outlet 608 which is in communication with afluid dispensing means shown here as including a fluid dispensing port610 (FIG. 49).

First base member 600 is also provided with a pair of longitudinallyextending flow passageways 611 the purpose for which will presently bedescribed. Passageways 611 communicate with a pair of transversechannels 612 (FIG. 48). Channels 612, in turn, communicate withreservoir inlet ports 613 of base member 601 which are of the characterbest seen in FIG. 48.

Reservoir outlet passageways for fluid flowing outwardly from thereservoir are provided in the form of longitudinally extending flowchannels 614 provided in a pair of protuberances 616 which areintegrally formed with base member 601. Channels 614, in turn,communicate with microchannels 617 of manifolds 602 and 604 via flowcontrol means, shown here as membrane assemblies 618 (FIG. 48) which aresuperimposed over manifolds 602 and 604 and micro-channels 617 in themanner shown in FIGS. 48 and 51. Assemblies 618 comprise an uppermicroporous layer 618a and a lower support layer 618b. With thisconstruction, when the device is in a fluid discharge mode, fluid whichis contained within reservoirs or chambers 620 (FIG. 51), such as adiluent containing the additive (the beneficial agent), is initiallyforced by the stored energy means through channels 614 provided inupstanding protuberances 616 formed on base member 601. As the liquidpasses through channels 614, it flows through flow control assemblies618 and into manifolds 602 and 604. After passing through the flow ratecontrol means, the beneficial agent flows through microchannels 617, andthence outwardly through outlet passageway 606. Passageway 606, in turn,communicates with dispensing means, shown here as including a connectorassembly 90.

The distendable membrane engagement means or protuberances 616 performthe sam function as previously described as does the unique storedenergy means. The stored energy means of this embodiment is of thegeneral character previously described and comprises a laminateassemblage 622 made up of at least two individual elements or membranes.As before, assemblage 622 cooperates with base member 601 to define thefluid chambers or reservoirs 620 (FIG. 51).

As indicated in FIG. 48, superimposed over the base and the storedenergy source is a structural cover 34 of the character previouslydescribed having appropriate medicant and medicant use instructionlabels 36. Affixed to the bottom of base member 600 is a cushioningmeans or pad 38 having adhesive on both sides. A peel strip 40 isconnected to the lower surface of pad 38. For certain applications, athin protective film may be affixed over cover 34 to prevent ingress ofliquids or other contaminants into the device.

Like the previously described embodiments, the present embodimentincludes filling means which enables chambers 620 to be filled with aselected parenteral liquid. Here the filling means includes a hypodermicsyringe and needle of the character identified in FIG. 58 by the numeral62 (see also FIG. 43).

As best seen in FIGS. 48, 53 and 57, base member 601 includes anupstanding, longitudinally extending portion 626 having a generallycylindrical chamber 628 extending therethrough (FIG. 57). In thisembodiment of the invention, chamber 628 is uniquely designed to closelyreceive the additive subassembly that sealably contains the additive tobe added to the parenteral fluid.

Referring to FIG. 52, this unique immobilized adding means or additivesubassembly comprises a glass tube or vial 630 which is sealed at eitherend by sealing means shown here as rubber stoppers 632 and 633. Stopper632 is adapted to sealably receive a piercing element such as thehypodermic needle 62a of syringe assembly 62. (FIGS. 52 and 53). Therubber stoppers 632 and 633 are preferably constructed of aself-sealing, noncoring, puncturable material such as silicone-SEBS.Tear open type aluminum sealing caps 637 are provided at each end oftube 630 and function to sealably encapsulate rubber stoppers 632 and633.

Sealing caps 637 comprise an aluminum sleeve portion 637a which iscrimped in place within a groove 630a provided at either end of tube orvial 630, and a removable end plate 637b. Disposed interiorly of tube630 is a substrate 640 which releasably carries the additive such as abeneficial agent of the character earlier defined herein (FIGS. 52, 55and 56). Substrate 640 which, along with the additive, comprises theadding means of this form of the invention can be of the same characteras the additive carriers of the assemblies shown in FIG. 45 andidentified by the numerals 425, 427, 429, 430, 433, 437 and 439. Asindicated in FIG. 59, vial 630 is provided with circumferentially spacedribs 630b which maintain the substrate spaced apart from the interiorwall of the vial. Such stand-off ribs may not be required whensubstrates of certain character are used.

Turning particularly to FIG. 60, it can be seen that a uniquelyconfigured needle 642 is integrally molded into base member 601. Needle642 is provided with first and second fluid passageways 644 and 646which are separated by a center section 645. Passageway 644 is incommunication at one of its ends with passageway 650 of base member 601.At its opposite end, passageway 644 communicates with the interior oftube 630 after the needle point 642a has pierced rubber stopper 633 in amanner shown in FIG. 59. Passageway 646 is in communication at one ofits ends with passageway 648 of base member 601 and at its opposite endcommunicates with outlet passageway 608 of base member 601 (FIG. 60).

In using the apparatus of the embodiment of the invention shown in FIGS.48 through 60, sealing caps 637 are opened in the manner shown in FIGS.52 and 56 to expose the site injection portion of the rubber stoppers.The adding means, or glass vial 630 is then inserted into chamber 628and urged forwardly with sufficient force to cause needle 642a topenetrate rubber stopper 633 in the manner shown in FIGS. 57 and 60. Asbest seen in FIG. 57, vial locking means, here shown as detents 651, areprovided at either end of chamber 628. These detents permit passage ofvial 630 in an inward direction but function to lock the vial in placeto prevent its withdrawal from the chamber.

With the vial locked in place within chamber 628, rubber stopper 632 ispierced by needle 62a of the needle syringe (FIG. 58) and the sterilediluent is introduced into the interior passageway 640a of substrate640. As indicated by the arrows in FIGS. 49 and 60, as the diluent flowslongitudinally of the additive presentation means, or substrate 640, itefficiently intermixes with the additive carried by the substrate. Themixture thus formed flows through passageway 644 of needle 642, intopassageway 650 (FIG. 60), through passageways 611 and 612 (FIG. 49) andthen into chambers 620 via ports 613. This fluid flow urges membranes622 outwardly into the position shown in FIG. 51 in close proximity withinterior walls 653 of porous body 655.

As before, the liquid, such as a parenteral fluid, which is introducedinto passageway 640a can include, by way of example, a reagent, asterile diluent, various electrolytes and various other aqueoussolutions.

After the additive carried by substrate 640 has been separate andreleased by the parenteral fluid and has been efficiently intermixedtherewith, the solution or beneficial agent thus formed will remainwithin reservoirs 620 until the time it is to be infused into thepatient. When the outlet port 610 is opened for fluid flow to thepatient, the fluid contained within chambers 620 will flow downwardlythrough channels 614 in protuberances 616, (FIG. 50), through the flowrate control membranes 618 and into crossing microchannels 617. As bestseen in FIG. 48 manifolds 602 and 604 communicate with transversemanifold passageways 606 which, in turn, are in communication with thefluid outlet port 610 of the device. A hydrophilic porous flow filter659 is disposed proximate the outlet end of substrate 640 (FIG. 55) forfiltering and controlling the residence time of the fluid within thesubstrate 640.

It is to be appreciated that a wide variety of additives, such as drugsand the like, can be removably affixed to substrates of widely varyingmaterial composition and design. The substrates can then be safelysealably contained within the sealed glass vial of the additivesubassembly for use at any later time with stored energy infusiondevices of the character shown in FIG. 48. This unique approach providesa completely new dimension to the preparation, packaging and controlledadministration of virtually any kind of beneficial agent to anambulatory patient.

Having now described the invention in detail in accordance with therequirements of the patent statutes, those skilled in this art will haveno difficulty in making changes and modifications in the individualparts or their relative assembly in order to meet specific requirementsor conditions. Such changes and modifications may be made withoutdeparting from the scope and spirit of the invention, as set forth inthe following claims.

I claim:
 1. A device for use in infusing fluids into an ambulatorypatient at a controlled rate comprising:(a) a base having a fluid inletand fluid outlet interconnected by a fluid flow path; (b) filling meansfor introducing fluid into said fluid inlet; (c) a distendable membraneconstructed of an elastic material which is fitted over said base todefine a chamber in communication with said fluid inlet and said fluidoutlet, said membrane being distendable by fluid introduced into saidchamber under pressure through said fluid inlet, said membrane having atendency to return to a substantially nondistended configuration wherebyfluid within said chamber will be expelled through said fluid outlet;and (d) adding means disposed within said fluid flow path for adding anadditive to fluid flowing therethrough.
 2. A device as defined in claim1 in which said adding means comprises an additive and an additivepresentation means for presenting said additive to the fluid, saidadditive presentation means being disposed within said fluid flow pathso that at least a part of said additive will be added to said fluidintroduced into said fluid inlet.
 3. A device as defined in claim 1 inwhich said adding means comprises an additive and an additivepresentation means for presenting said additive to the fluid, saidadditive presentation means having exposed surfaces, said additive beingremovably connected to said exposed surfaces.
 4. A device as defined inclaim 1 in which said adding means comprises a structural support havingexposed surfaces and a beneficial agent present on said exposed surfacessaid structural support being disposed within said fluid flow path sothat at least a portion of said beneficial agent will be added to saidfluid introduced into said fluid inlet.
 5. A device as defined in claim1 in which said adding means comprises a polymer support and an additivecarried by said polymer support, said polymer support being disposedwithin said fluid flow path so that at least a portion of said additivewill be added to the fluid flowing through said fluid flow path.
 6. Adevice as defined in claim 1 in which said adding means comprises amember having exposed surfaces and a biologically active materialpresent on said exposed surfaces, said member being disposed within saidfluid flow path so that said biologically active material will be addedto said fluid introduced into said fluid inlet.
 7. A device as definedin claim 1 in which said distendable membrane comprises a plurality oflayers of an elastic material one said layer being in contact with thefluid introduced by said filling means.
 8. A device as defined in claim1 further including at least one fluid flow control means disposedinternally of said chamber for controlling the rate of flow of fluidtoward said fluid outlet.
 9. A device as defined in claim 8 furtherincluding means disposed intermediate said distendable membrane and saidfluid flow control means for creating an ullage within said chamber. 10.A device as defined in claim 8 in which said fluid flow control meanscomprises a thin film, planar shaped permeable membrane.
 11. A device asdefined in claim 8 in which said fluid flow control means comprisesfirst and second permeable members, each of said permeable membershaving different permeability, whereby the rate of fluid flow along saidfluid flow path is controllably regulated.
 12. A device as defined inclaim 8 further including infusion means connected to said fluid outletfor infusing fluid into the patient.
 13. A device as defined in claim 12in which said filling means comprises a self-sealing, puncturable septumdisposed within said fluid inlet.
 14. A device for use in infusingfluids into an ambulatory patient at a controlled rate comprising:(a) abase having a fluid inlet, a fluid outlet and a fluid passagewayinterconnecting said fluid inlet and said fluid outlet; (b) fillingmeans for introducing fluid into said fluid inlet; (c) a distendablemembrane constructed of an elastic material which is fitted over saidbase to define a chamber in communication with said fluid passageway,and with said membrane being distendable by fluid introduced into saidchamber under pressure through said fluid inlet and having a tendency toreturn to a substantially nondistended configuration whereby fluidwithin said chamber will be expelled through said fluid outlet; (d)adding means disposed within said fluid passageway for adding anadditive to fluid flowing therethrough, said adding means comprising asupport and an additive removably connected to said support; and (e)infusion means communicating with said fluid passageway for infusingfluid into the patient.
 15. A device as defined in claim 14 in whichsaid support has an exposed region, said additive being present at saidregion, said support being disposed within said fluid passageway so thatsaid additive will be added to said fluid flowing therethrough.
 16. Adevice as defined in claim 15 in which said additive includes an activesurface agent.
 17. A device as defined in claim 15 in which said supportextends transversely of said base.
 18. A device as defined in claim 15in which said support extends longitudinally of said base.
 19. A deviceas defined in claim 15 in which said support comprises a body havinginterstitial voids.
 20. A device as defined in claim 15 in which saidsupport comprises a solid member and in which said exposed regioncomprises an exposed surface on said member, said additive beingdeposited on said surface.
 21. A device as defined in claim 15 in whichsaid support comprises a body comprising a multiplicity of microporouspolymers.
 22. A device as defined in claim 15 in which said supportcomprises a body constructed from high porosity, semi-syntheticcelullosics.
 23. A device as defined in claim 15 in which said supportcomprises a plurality of spaced apart porous disk shaped wafers eachsaid wafer having a site exhibiting an additive.
 24. A device as definedin claim 15 in which said support comprises a body formed of a porousceramic material.
 25. A device as defined in claim 15 in which saidsupport comprises a crystal sponge.
 26. A device as defined in claim 15in which said support comprises a body constructed from a multiplicityof porous glass beads.
 27. A device as defined in claim 15 in which saidadditive comprises a drug.
 28. A device as defined in claim 15 in whichsaid additive comprises a biologically active material.
 29. A device asdefined in claim 15 in which said additive comprises a chemicalcompound.
 30. A device as defined in claim 15 in which said supportcomprises an azlactone functional polymer.
 31. A device for use ininfusing beneficial agents into a patient at a controlled ratecomprising:(a) a base having a fluid inlet, a fluid outlet and a fluidpassageway interconnecting said fluid inlet and said fluid outlet; (b)filling means for introducing fluid into said fluid inlet; (c) adistendable membrane constructed of an elastic material which is fittedover said base to define a chamber in communication with said fluidpassageway, said membrane being distendable by fluid introduce into saidchamber under pressure through said fluid passageway and having atendency to return to a substantially nondistended configuration wherebyfluid within said chamber will be expelled through said fluid outlet;(d) adding means mounted within said base for adding an additive tofluid introduced by said filling means, said adding means comprising:(i)additive presentation means disposed within said fluid passageway forpresenting an additive to the fluid flowing therethrough; and (ii) anadditive removably interconnected to said additive presentation means,said additive comprising a beneficial agent.
 32. A device as defined inclaim 31 in which said adding means comprises a vial assembly havingsaid additive presentation means sealably contained therein.
 33. Adevice as defined in claim 32 in which said additive presentation meanscomprises a functional substrate and in which said additive comprises abeneficial agent removably affixed to said functional substrate.
 34. Adevice as defined in claim 33 in which said vial assembly comprises aglass vial having first and second ends sealed by first and secondsealing members.
 35. A device as defined in claim 34 in which said baseincludes a longitudinally extending chamber for receiving said glassvial.
 36. A device as defined in claim 35 in which a hollow needle ismounted within said longitudinally extending chamber for piercing saidsecond sealing member, said hollow needle having a fluid passageway incommunication with said fluid passageway of said base.
 37. A device asdefined in claim 36 further including vial locking means for lockingsaid vial within said longitudinally extending chamber of said base. 38.A device as defined in claim 36, further including end caps sealablyreceivable over said first and second sealing members.
 39. A device asdefined in claim 36 in which said filling means comprises a hollowneedle interconnected with a source of fluid, said hollow needle beingadapted to pierce said first sealing member of said vial assembly.
 40. Adevice for use in infusing fluids into an ambulatory patient at acontrolled rate comprising:(a) a base having a fluid inlet and fluidoutlet interconnected by a fluid flow path; (b) filling means forintroducing fluid into said fluid inlet; (c) a distendable membraneconstructed of an elastic material which is fitted over said base todefine a chamber in communication with said fluid inlet and said fluidoutlet, said membrane being distendable by fluid introduced into saidchamber under pressure through said fluid inlet, said membrane having atendency to return to a substantially nondistended configuration wherebyfluid within said chamber will be expelled through said fluid outlet;and (d) adding means disposed within said fluid flow path for adding anadditive to fluid flowing therethrough, said adding means comprising anadditive and an additive presentation means for presenting said additiveto the fluid, said additive presentation means being disposed withinsaid fluid flow path so that at least a part of said additive will beadded to said fluid introduced into said fluid inlet.
 41. A device asdefined in claim 40 in which said distendable membrane includes asurface in contact with the fluid introduced by said filling means andin which said additive is removably interconnected with said surface.42. A device as defined in claim 40 in which said additive presentationmeans comprises a flow rate control membrane disposed between said fluidoutlet of said base and said chamber, said flow rate control membranehaving exposed surfaces, said additive being removably connected to saidexposed surfaces.
 43. A device as defined in claim 40 in which saidadditive presentation means comprises a surface on said base, saidadditive being removably connected to said surface.